Optic nerve damage and regeneration failure are major features of glaucoma, inherited and traumatic optic neuropathies, and other blinding diseases. Developing strategies to promote anatomical regeneration and functional re-connection of injured optic nerve has been a long-standing challenge. By using an intraorbital optic nerve injury model in adult mice, we discovered that conditional deletion of SOCS3 and PTEN/TSC1 in RGCs promotes significant neuronal survival and axon regeneration. Our further studies suggested mTOR as a critical mediator of axon regeneration after PTEN/TSC1 deletion, likely by controlling the ability of injured neurons to synthesize materials for axon growth. On the other side, our data suggested that axon regeneration after SOCS3 deletion depends on gp130 signaling. In this proposal, we will address the following questions: First, what is the effector of SOCS deletion in promoting neuronal survival and axon regeneration and whether SOCS3 is the only key negative regulator? Second, do SOCS3-dependent and PTEN/TSC1-dependent pathways interact? Third, are regenerating axons able to find their pathway and mediate functional recovery? We expect that these experiments will provide important insights into the understanding the mechanisms of optic axon regeneration and the development of neural repair therapeutics. PUBLIC HEALTH RELEVANCE: Optic nerve damage and regeneration failure are major features of glaucoma, inherited and traumatic optic neuropathies, and other blinding diseases. Developing strategies to promote anatomical regeneration and functional re-connection of injured optic nerve has been a long-standing challenge. By AAV-Cre-assisted conditional knockout of floxed mouse genes, we recently made an exciting discovery that deletion of SOCS3 (suppressor of cytokine signaling 3) in adult retinal ganglion cells (RGCs) enables robust long-distance axon regeneration after intraorbital optic nerve injuries, revealing a potentially important signaling pathway in regulating axon regenerative ability of mature CNS neurons. The objectives of this proposed study are two-folds: to determine the underlying mechanisms permitting axon regeneration in SOCS3-deleted neurons and to assess whether the regenerating axons could find the normal projection pathway and re-form synaptic connections with their central targets.